Prescription Drug Information: Albuterol Sulfate

ALBUTEROL SULFATE- albuterol sulfate solution
A-S Medication Solutions

DESCRIPTION

Albuterol Sulfate Inhalation Solution, 0.5% is a sterile solution that contains albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta2 -adrenergic bronchodilator (see CLINICAL PHARMACOLOGYsection below). Albuterol sulfate has the chemical name α1 -[(tert -Butylamino) methyl]-4-hydroxy-m -xylene-α,α’-diol sulfate (2:1) (salt), and the following structural formula:

Chemical Structure
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Albuterol sulfate has a molecular weight of 576.71 and the molecular formula (C13 H21 NO3 )2 •H2 SO4 . Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol.

The World Health Organization’s recommended name for albuterol base is salbutamol.

Albuterol Sulfate Inhalation Solution, 0.5% is in concentrated form. Dilute the appropriate volume of the solution (see DOSAGE AND ADMINISTRATION) with sterile normal saline solution to a total volume of 3 mL and administer by nebulization.

Each mL Contains: ACTIVE: Albuterol sulfate equivalent to 5 mg of albuterol in an aqueous solution. Sulfuric Acid may be added to adjust pH (3.5-4.2).

PRESERVATIVE ADDED: Benzalkonium Chloride 0.01%. Albuterol sulfate inhalation solution contains no sulfiting agents. It is supplied in 20 mL bottles.

Albuterol Sulfate Inhalation Solution is a clear, colorless sterile solution.

CLINICAL PHARMACOLOGY

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2 — receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established (see WARNINGS).

The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’,5’-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects.

Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O -methyl transferase.

Pharmacokinetics

Studies in asthmatic patients have shown that less than 20% of a single albuterol dose was absorbed following either intermittent positive-pressure breathing (IPPB) or nebulizer administration; the remaining amount was recovered from the nebulizer and apparatus and expired air. Most of the absorbed dose was recovered in the urine within 24 hours after drug administration. Following a 3-mg dose of nebulized albuterol in adults, the maximum albuterol plasma levels at 0.5 hours were 2.1 ng/mL (range, 1.4 to 3.2 ng/mL). There was a significant doserelated response in FEV1 (forced expiratory volume in 1 second) and peak flow rate. It has been demonstrated that following oral administration of 4 mg of albuterol, the elimination half-life was 5 to 6 hours.

Preclinical

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Clinical Trials

In controlled clinical trials in adults, most patients exhibited an onset of improvement in pulmonary function within 5 minutes as determined by FEV1 . FEV1 measurements also showed that the maximum average improvement in pulmonary function usually occurred at approximately 1 hour following inhalation of 2.5 mg of albuterol by compressor-nebulizer and remained close to peak for 2 hours. Clinically significant improvement in pulmonary function (defined as maintenance of a 15% or more increase in FEV1 over baseline values) continued for 3 to 4 hours in most patients, with some patients continuing up to 6 hours.

Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant improvement in either FEV1 or PEFR within 2 to 20 minutes following single doses of albuterol inhalation solution. An increase of 15% or more in baseline FEV1 has been observed in children aged 5 to 11 years up to 6 hours after treatment with doses of 0.10 mg/kg or higher of albuterol inhalation solution. Single doses of 3, 4, or 10 mg resulted in improvement in baseline PEFR that was comparable in extent and duration to a 2-mg dose, but doses above 3 mg were associated with heart rate increases of more than 10%.

INDICATIONS AND USAGE

Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 2 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm.

CONTRAINDICATIONS

Albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.

WARNINGS

Paradoxical Bronchospasm:

Albuterol sulfate inhalation solution can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, albuterol sulfate inhalation solution should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.

Albuterol sulfate inhalation solution contains the preservative benzalkonium chloride. Benzalkonium chloride has been associated with bronchospasm in a dose-dependent manner. In patients who receive high doses (e.g., continuous nebulization) of albuterol sulfate inhalation solution and bronchospasm does not resolve, consider a trial of short-acting bronchodilator that does not contain the preservative benzalkonium chloride [see Dosage and Administration ].

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs and with the home use of nebulizers. It is therefore essential that the physician instruct the patient in the need for further evaluation if his/her asthma becomes worse.

Cardiovascular Effects: Albuterol sulfate inhalation solution, like all other betaadrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of albuterol sulfate inhalation solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTC interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, albuterol sulfate inhalation solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of albuterol sulfate inhalation solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of albuterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema.

Use of Anti-inflammatory Agents: The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids.

Microbial Contamination: It is recommended that each multi-dose bottle of albuterol be used for only one patient. Nosocomial outbreaks of pneumonia have occurred in hospitals when one multi-dose bottle of albuterol was used to treat more than one patient. To avoid microbial contamination, proper aseptic technique should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used.

PRECAUTIONS

General

Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmia; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines.

Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.

Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

Repeated dosing with 0.15 mg/kg of albuterol inhalation solution in children aged 5 to 17 years who were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum potassium levels.

To avoid contaminating the multi-dose bottle of albuterol sulfate inhalation solution for inhalation, proper aseptic technique should be used when withdrawing and delivering the dose into the nebulizer.

Information for Patients

The action of albuterol sulfate inhalation solution may last up to 6 hours or longer. Albuterol sulfate inhalation solution should not be used more frequently than recommended. Do not increase the dose or frequency of albuterol sulfate inhalation solution without consulting your physician. If you find that treatment with albuterol sulfate inhalation solution becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using albuterol sulfate inhalation solution, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of albuterol sulfate inhalation solution. Effective and safe use of albuterol sulfate inhalation solution includes an understanding of the way that it should be administered.

Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in a nebulizer have not been established.

See illustrated Patient’s Instructions for Use.”

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